2-&#39;4-(Hydroxymethyl-phenylamino)-piperidine-1-yl!-n-(9h-carbazol-3-yl) - acetamine derivatives and related compounds as neuropeptide y5 (npy5) ligands for the treatment of obesity

ABSTRACT

The present invention relates to 1,4-disubstituted piperidine compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals. The substituents are as defined in the present claim  1.

The present invention relates to 1,4-disubstituted piperidine compoundsof general formula (I), methods for their preparation, medicamentscomprising these compounds as well as their use for the preparation of amedicament for the treatment of humans or animals.

Neuropeptide Y (NPY), first isolated in porcine brain extracts (Tatemotoet. al. Nature 1982, 296, 659), is a 36-aminoacid peptide belonging tothe family of pancreatic polypeptides, and is one of the most abundantpeptides in the brain and in the central nervous system. Several studiessuggest that NPY plays a significant role in cognitive functionregulation, e.g. memory (Flood J. F. et. al. Brain Res. 1987, 421, 280;Redrobe J. P. et. Al. Brain Res. 1999, 848, 153), and in the developmentof anxiety (Heilig M. et. al. Reg. Peptides 1992, 41, 61) and depression(Heilig M. et. al. Eur. J. Pharmacol. 1988, 147, 465).

Moreover, NPY is also distributed in the peripheral system and somestudies suggest that it is involved in hypertensive (Michel M. C: et.al. J. Hypertens. 1995,13, 385), and analgesic (Gehlert D. R. Life Sci.1994, 55, 551) processes, among others.

The endogenous proteins that constitute NPY-binding receptors have beenwidely studied. Several have been cloned and expressed. At present, sixdifferent receptor subtypes, named Y1 to Y6, are recognized (Hispkind P.A. et. al. Annu. Rep. Med. Chem. 1996, 31, 1; Grundemar L. et. al. TIPSReviews., 15, 153, 1994). Each NPY receptor subtype is generallyassociated to a different biological activity.

The most recently identified receptor is Y5 (Hu et. al. J. Biol. Chem.1996, 271, 26315). Since there is ample evidence that the Y5 receptorhas a unique pharmacological profile compared to the other receptorsubtypes, it was initially expected that the Y5 receptor might be asuitable target for the treatment of food intake related disorders suchas obesity. This attitude has changed and it is now the common opinionamong those skilled in the art that the Y5 receptor in general is not asuitable target for a treatment of food intake related disorders such asobesity. This change in attitude may be attributed to the fact that thecompounds with affinity for the NPY-5 receptor tested so far were notorally active, see also Current Opinion in Investigational Drugs 2003,4, 1198; Diabetes Vol. 51, August 2002, 2441 and International Journalof Obesity 2004, 28, 628.

Thus, it was an object of the present invention to provide novelcompounds that are suitable in particular as active substances inmedicaments, preferably in medicaments for the regulation ofneuropeptide Y receptors, particularly preferably of neuropeptide Y 5(NPY5) receptor, for the regulation of food intake and for theprophylaxis and/or treatment of food intake related disorders such asobesity, anorexia, cachexia, bulimia or type II (non insulin dependent)diabetes.

Surprisingly, it has been found that the 1,4-disubstituted piperidinecompounds of general formula (I) given below have affinity forneuropeptide Y receptors, in particular for neuropeptide Y 5 (NPY5)receptors. Moreover, the compounds according to the present inventionhave surprisingly been found to show significant appetite suppressingeffects.

Therefore, in one of its aspects the present invention relates to1,4-disubstituted piperidine compounds of general formula (I),

wherein

a represents 0, 1, 2, 3 or 4,

b represents 0, 1, 2 or 3,

c represents 0, 1, 2, 3 or 4,

R¹, R², R³, R⁴ are each independently selected from the group consistingof hydrogen; halogen; —CN; —NO₂; —OR⁸; a linear or branched, saturatedor unsaturated, optionally at least mono-substituted aliphatic radical;a saturated or unsaturated, optionally at least mono-substituted,optionally at least one heteroatom as ring member containingcycloaliphatic radical, which may be bonded via an alkylene group; or anoptionally at least mono-substituted aryl- or heteroaryl radical, whichmay be bonded via an alkylene group and/or which may be condensed withan optionally at least mono-substituted, saturated or unsaturated mono-or bicyclic ring system,

R⁵ represents hydrogen, a linear or branched, saturated or unsaturated,optionally at least mono-substituted aliphatic radical, or a saturatedor unsaturated, optionally at least mono-substituted cycloaliphaticradical,

R⁶, R⁷ and R⁸, identical or different, each represent hydrogen or aprodrug-moiety,

A represents a —CH₂— or —CH₂—CH₂— group,

optionally in form of one of its stereoisomers, preferably enantiomersor diastereomers, its racemate or in form of a mixture of at least twoof its stereoisomers, preferably enantiomers or diastereomers, in anymixing ratio, or a salt, preferably a physiologically acceptable saltthereof, or a corresponding solvate, respectively.

Preferred are 1,4-disubstituted piperidine compounds of general formula(I) given above, wherein

a represents 0, 1, 2, 3 or 4,

b represents 0, 1, 2 or 3,

c represents 0, 1, 2, 3 or 4,

R¹, R², R³, R⁴ are each independently selected from the group consistingof H; F; Cl; Br; —CN; —NO₂; —OR⁸; a linear or branched, saturated orunsaturated, optionally at least mono-substituted C₁₋₆-aliphaticradical; a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₃-₈-cycloaliphatic radical, which may be bonded via aC₁₋₃-alkylene group; or an optionally at least mono-substituted aryl- orheteroaryl radical, which may be bonded via a C₁₃-alkylene group and/orwhich may be condensed with an optionally at least mono-substituted,saturated or unsaturated mono- or bicyclic ring system,

R⁵ represents hydrogen, a linear or branched, saturated or unsaturated,optionally at least mono-substituted C₁₋₆aliphatic radical, or asaturated or unsaturated, optionally at least mono-substitutedC₃₋₈-cycloaliphatic radical,

R⁶, R⁷ and R⁸, identical or different, each represent hydrogen or aprodrug-moiety,

A represents a —CH₂- or —CH₂—CH₂— group,

optionally in form of one of its stereoisomers, preferably enantiomersor diastereomers, its racemate or in form of a mixture of at least twoof its stereoisomers, preferably enantiomers or diastereomers, in anymixing ratio, or a salt, preferably a physiologically acceptable saltthereof, or a corresponding solvate, respectively.

A prodrug moiety in the sense of the present invention is a moiety thatwill give rise to a pharmacologically active metabolite of therespective compound of general formula I in vivo.

Suitable prodrug moieties, methods for their preparation, methods fortheir introduction into a starting compound to give a compound ofgeneral formula I as defined above as well as methods for determinationof the metabolite formed in vivo are well known to those skilled in theart, e.g. from the textbooks of Krogsgaard-Larsen, Povl, “A textbook ofdrug design and development” Harwood Academic (ISBN 3-7186-5100-9) andfrom Bernard Testa and Joachim B. Mayer, “Hydrolysis in drug and prodrugmetabolism: Chemistry, biochemistry and enzymology, Wiley-VCH, 2003,Weinheim (ISBN-3-906390-25-X). The respective parts of the literaturedescription are hereby incorporated by reference and form part of thepresent disclosure.

A mono- or bicyclic ring system according to the present invention meansa mono- or bicyclic hydrocarbon ring system that may be saturated,unsaturated or aromatic. If the ring system is bicyclic, each of itsdifferent rings may show a different degree of saturation, i.e. it maybe saturated, unsaturated or aromatic. Optionally each of the rings ofthe mono- or bicyclic ring system may contain one or more heteroatoms asring members, which may be identical or different and which canpreferably be selected from the group consisting of N, O, S and P, morepreferably be selected from the group consisting of N, O and S. Saidmono- or bicyclic ring-system may preferably contain 0, 1, 2 or 3heteroatoms chosen from the afore mentioned group, preferably itcontains 0 or 1 heteroatoms chosen from the afore mentioned group. Therings of the mono- or bicyclic ring system are preferably 5- or6-membered.

Those skilled in the art understand that the term “condensed” indicatesthat the condensed rings share more than one atom. The terms “annulated”or “fused” may also be used for this type of bonding.

If one or more of the residues R¹—R⁵ represents an aliphatic radical,which is substituted by one or more substituents, unless definedotherwise, each of these substituents may preferably be selected fromthe group consisting of hydroxy, halogen, branched or linearC₁₋₄-alkoxy, branched or linear C₁₋₄-perfluoroalkoxy, branched or linearC₁₋₄-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂,—CO—C₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl, —NH—SO₂—C₁₋₄-alkyl ,wherein the C₁₋₄-alkyl may in each case be branched or linear, anunsubstituted or at least mono-substituted phenyl or naphthyl radicaland an unsubstituted or at least mono-substituted furanyl-, thienyl-,pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-,quinolinyl- and isoquinolinyl radical, more preferably be selected fromthe group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃ and anunsubstituted phenyl radical. If any one of these substituents itself isat least mono-substituted, said substituents may preferably be selectedfrom the group consisting of F, Cl, methyl and methoxy. Preferably thesubstituted alkyl radical may be substituted with 1, 2, 3, 4 or 5, morepreferably with 1, 2 or 3 of the afore mentioned substituents.

If one or more of the residues R¹—R⁵ represents or comprises acycloaliphatic radical, which is substituted by one or moresubstituents, unless defined otherwise, each of these substituents maypreferably be selected from the group consisting of hydroxy, halogen,branched or linear C₁₋₄-alkyl, branched or linear C₁₋₄-alkoxy, branchedor linear C₁₋₄-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branchedor linear C₁₋₄-perfluoroalkyl, —NR^(A)R^(B) wherein R^(A), R^(B) areeach independently selected from the group consisting of H, a branchedor linear C₁₋₄-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido,cyano, nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl, —CO—OC₁₋₄-alkyl, —SO—C₁₋₄-alkyl,—SO₂—C₁₋₄-alkyl, —NH—SO₂—C₁₋₄-alkyl, wherein C₁₋₄-alkyl may in each casebe branched or linear, unsubstituted or at least mono-substituted phenylor naphthyl and an unsubstituted or at least mono-substituted furanyl-,thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-,quinolinyl- and isoquinolinyl radical, more preferably be selected fromthe group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy,ethoxy, benzoyl, phenoxy, cyclohexyl, —CF₃, —CO—CH₃, —CO—OCH₃,—NR^(A)R^(B) wherein R^(A), R^(B) are each independently selected fromthe group consisting of H, a branched or linear C₁₋₄-alkyl-radical,—CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any oneof these substituents itself is at least mono-substituted, saidsubstituents may preferably be selected from the group consisting of F,Cl, methyl and methoxy. Preferably the substituted cycloaliphaticradical may be substituted with 1, 2, 3, 4 or 5, more preferably with 1,2 or 3 of the afore mentioned substituents.

If one or more of the residues R¹—R⁴ comprises a mono- or bicycyclicring system, which is substituted by one or more substituents, unlessdefined otherwise, each of these substituents may preferably be selectedfrom the group consisting of hydroxy, halogen, branched or linearC₁₋₄-alkyl, branched or linear C₁₋₄-alkoxy, branched or linearC₁₋₄-perfluoroalkoxy, branched or linear C₁₋₄-perfluoroalkyl, amino,carboxy, amido, cyano, keto, nitro, —SO₂NH₂, —CO—C₁₋₄-alkyl,-SO-C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl, —NH—SO₂—C₁₋₄-alkyl, wherein C₁₋₄-alkylmay be branched or linear, an unsubstituted or at least mono-substitutedphenyl or naphthyl radical and unsubstituted or at leastmono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-,pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferablyfrom the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy,ethoxy, CF₃, keto (═O), cyano and an unsubstituted phenyl radical. Ifany one of these substituents itself is at least mono-substituted, saidsubstituents may preferably be selected from the group consisting of F,Cl, methyl and methoxy. Preferably the substituted mono- or bicycyclicringsystem may be substituted with 1, 2, 3, 4 or 5, more preferably with1, 2 or 3 of the afore mentioned substituents.

If one or more of the residues R¹—R⁴ represents or comprises an arylradical, which is substituted by one or more substituents, unlessdefined otherwise, each of these substituents may preferably be selectedfrom the group consisting of hydroxy, halogen, branched or linearC₁₋₄-alkoxy, branched or linear C₁₋₄-alkyl, branched or linearC₁₋₄-perfluoroalkoxy, unsubstituted or at least mono-substitutedphenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl,branched or linear C₁₋₄-perfluoroalkyl, NR^(A)R^(B) wherein R^(A), R^(B)are each independently selected from the group consisting of H, abranched or linear C₁₋₄-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy,amido, cyano, —C(H)(OH)(phenyl), —C(H)(OH)(CH₃), nitro, —SO₂NH₂,—CO—C₁₋₄-alkyl, —CO—OC₁₋₄-alkyl, —SO—C₁₋₄-alkyl, —SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein C₁₋₄-alkyl may be branched or linear, anunsubstituted or at least mono-substituted phenyl or naphthyl radicaland unsubstituted or at least mono-substituted furanyl-, thienyl-,pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-,quinolinyl- and isoquinolinyl radical, more preferably be selected fromthe group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano,—C(H)(OH)(phenyl), —C(H)(OH)(CH₃), methoxy, ethoxy, unsubstituted or atleast mono-substituted benzoyl, unsubstituted or at leastmono-substituted phenoxy, cyclohexyl, CF₃, —CO—CH₃, —CO—OCH₃,—NR^(A)R^(B) wherein R^(A), R^(B) are each independently selected fromthe group consisting of H, a branched or linear C₁₋₄-alkyl-radical,—CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any ofthese substituents itself is at least mono-substituted, saidsubstituents may preferably be selected from the group consisting of F,Cl, methyl and methoxy. Preferably the substituted aryl radical may besubstituted with 1, 2, 3, 4 or 5, more preferably with 1, 2 or 3 of theafore mentioned substituents.

If one or more of the residues R¹—R⁴ represents or comprises aheteroaryl radical, which is substituted by one or more substituents,unless defined otherwise, each of these substituents may preferably beselected from the group consisting of hydroxy, halogen, branched orlinear C₁₋₄-alkoxy, branched or linear C₁₋₄-alkyl, branched or linearC₁₋₄-perfluoroalkoxy, unsubstituted or at least mono-substitutedphenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl,branched or linear C₁₋₄-perfluoroalkyl, NR^(A)R^(B) wherein R^(A), R^(B)are each independently selected from the group consisting of H, abranched or linear C₁₋₄-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy,amido, cyano, nitro, —C(H)(OH)(phenyl), —C(H)(OH)(CH₃), —SO₂NH₂,—CO—C₁₋₄-alkyl, —CO—OC₁₋₄-alkyl, SO—C₁₋₄-alkyl, SO₂—C₁₋₄-alkyl,—NH—SO₂—C₁₋₄-alkyl, wherein C₁₋₄-alkyl may be branched or linear, anunsubstituted or at least mono-substituted phenyl or naphthyl radicaland an unsubstituted or at least mono-substituted furanyl-, thienyl-,pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-,quinolinyl- and isoquinolinyl radical, more preferably be selected fromthe group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano,methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl,unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF₃,—C(H)(OH)(phenyl), —C(H)(OH)(CH₃), —CO—CH₃, —CO—OCH₃, —NR^(A)R^(B)wherein R^(A), R^(B) are each independently selected from the groupconsisting of H, a branched or linear C₁₋₄-alkyl-radical, —CH₂—CH₂—OHand phenyl, and an unsubstituted phenyl radical. If any one of thesesubstituents itself is at least mono-substituted, said substituents maypreferably be selected from the group consisting of F, Cl, methyl andmethoxy. Preferably the substituted heteroaryl radical may besubstituted with 1, 2, 3, 4 or 5, more preferably with 1, 2 or 3 of theafore mentioned substituents.

Alkylene groups according to the present invention may preferably beselected from the group consisting of —CH₂—, —CH₂—CH₂—, —CH(CH₃)—,—CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, —CH₂—CH₂—CH(CH₃)—,—C(CH₃)₂—CH₂—CH₂—, —CH₂‘CH₂—C(CH₃)₂— and —CH₂—CH₂—CH₂—CH₂.

If one or more of the residues R¹—R⁵ represents or comprises acycloaliphatic radical, which contains one or more heteroatoms as ringmembers, unless defined otherwise, each of these heteroatoms maypreferably be selected from the group consisting of N, O, S and P, morepreferably from the group consisting of N, O and S. Said cycloaliphaticradical may preferably contain 0, 1, 2 or 3 heteroatoms chosen from theafore mentioned group, more preferably it contains 0 or 1 heteroatomschosen from the afore mentioned group.

If one or more of the residues R¹—R⁴ represents or comprises anheteroaryl radical, which contains one or more heteroatoms as ringmembers, unless defined otherwise, each of these heteroatoms maypreferably be selected from the group consisting of N, O, S and P, morepreferably from the group consisting of N, O and S. Said heteroarylradical may preferably contain 1, 2 or 3 heteroatoms chosen from theafore mentioned group, preferably it contains 1 or 2 heteroatoms chosenfrom the afore mentioned group.

Preferred are compounds of general formula (1), wherein R¹, R², R³, R⁴are each independently selected from the group consisting of H; F; Cl;Br; —CN; —NO₂; —OR⁸; a linear or branched, optionally at leastmono-substituted C₁₋₄-alkyl radical, a saturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₅- or C₆- cycloaliphatic radical, which may be bonded via anoptionally at least mono-substituted C₁- or C₂-alkylene group;

more preferably R¹, R², R³, R⁴ are each independently selected from thegroup consisting of H; F; Cl; Br; —CN; —NO₂; —CH₃; —CH₂CH₃; —CHF₂;—CH₂F; —CF₃; —CF₂CF₃; OR⁸; cyclopentyl and cyclohexyl,

even more preferably R¹, R², R³, R⁴ are each independently selected fromthe group consisting of H; F; Cl; Br, CH₃ and OR⁸ and R⁵—R⁸, A, a, b andc have the meaning given above, optionally in form of one of theirstereoisomers, preferably enantiomers or diastereomers, their racematesor in form of a mixture of at least two of its stereoisomers, preferablyenantiomers or diastereomers, in any mixing ratio, or salts, preferablyphysiologically acceptable salts thereof, or corresponding solvates,respectively.

Also preferred are compounds of general formula (1), wherein R⁵represents H or a linear or branched C₁₋₆ alkyl radical,

more preferably R⁵ represents H or an alkyl radical selected from thegroup consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl and tert-butyl and R¹—R⁴, R⁶—R⁸, A, a, b and c havethe meaning given above, optionally in form of one of theirstereoisomers, preferably enantiomers or diastereomers, their racematesor in form of a mixture of at least two of its stereoisomers, preferablyenantiomers or diastereomers, in any mixing ratio, or salts, preferablyphysiologically acceptable salts thereof, or corresponding solvates,respectively.

Also preferred are compounds of general formula (I), wherein R⁶, R⁷ andR⁸, identical or different, each represent H or a prodrug-moietyselected from the group consisting of

linear or branched C₁₋₃-alkyl,

a P(═O)(OR⁹)₂ group, wherein R⁹ represents a linear or branchedC₁₋₄-alkyl radical,

a —(C═O)—O—R¹⁰ group, wherein R¹⁰ represents a linear or branchedC₁₋₅-alkyl radical,

a —(C═O)—NH—R¹¹ group, wherein R¹¹ represents a phenyl group, which ismono-substituted with a linear or branched C₁₋₃ alkyl radical,

a —(C═O)—R¹² group, wherein R¹² represents a phenyl group, which ismono-substituted with a —O—(C═O)—C₁₋₃-alkyl radical, an—CH₂—N(C₁₋₄-alkyl)₂ group or a

and R¹—R⁵, A, a, b and c have the meaning given above, optionally inform of one of their stereoisomers, preferably enantiomers ordiastereomers, their racemates or in form of a mixture of at least twoof its stereoisomers, preferably enantiomers or diastereomers, in anymixing ratio, or salts, preferably physiologically acceptable saltsthereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (1), wherein R⁶, R⁷ andR⁸, identical or different, each represent H or a prodrug-moietyselected from the group consisting of

linear or branched C₁₋₃-alkyl,

a P(═O)(OR⁹)₂ group, wherein R⁹ represents methyl or ethyl,

a —(C═O)O—R¹⁰ group, wherein R¹⁰ represents an alkyl radical selectedfrom the group consisting of methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl and tert-butyl,

a —(C═O)—NH—R¹¹ group, wherein R¹¹ represents a phenyl group, which ismono-substituted with methyl or ethyl,

a —(C═O)—R¹² group, wherein R¹² represents a phenyl group, which ismono-substituted with —O—(C═O)—C₁₋₃-alkyl radical in the ortho positionor with an —CH₂—N(C₁₋₄-alkyl)₂ in the meta or para position or with a

in the meta or para position and R¹—R⁵, A, a, b and c have the meaninggiven above, optionally in form of one of their stereoisomers,preferably enantiomers or diastereomers, their racemates or in form of amixture of at least two of its stereoisomers, preferably enantiomers ordiastereomers, in any mixing ratio, or salts, preferably physiologicallyacceptable salts thereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (1), wherein R⁶, R⁷ andR⁸ each represent hydrogen and R¹—R⁵, A, a, b and c have the meaninggiven above, optionally in form of one of their stereoisomers,preferably enantiomers or diastereomers, their racemates or in form of amixture of at least two of its stereoisomers, preferably enantiomers ordiastereomers, in any mixing ratio, or salts, preferably physiologicallyacceptable salts thereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (I), wherein Arepresents a —CH₂—group and R¹—R⁴, R⁵, R⁶—R⁸, a, b and c have themeaning given above, optionally in form of one of their stereoisomers,preferably enantiomers or diastereomers, their racemates or in form of amixture of at least two of its stereoisomers, preferably enantiomers ordiastereomers, in any mixing ratio, or salts, preferably physiologicallyacceptable salts thereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (I), wherein arepresents 1, 2 or 3, more preferably 1 or 2, even more preferably 1 andR¹—R⁴, R5, R⁶—R⁸, A, b and c have the meaning given above, optionally inform of one of their stereoisomers, preferably enantiomers ordiastereomers, their racemates or in form of a mixture of at least twoof its stereoisomers, preferably enantiomers or diastereomers, in anymixing ratio, or salts, preferably physiologically acceptable saltsthereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (I), wherein brepresents 0, 1 or 2, more preferably 0 or 1 and R¹—R⁴, R⁵, R⁶—R⁸, A, aand c have the meaning given above, optionally in form of one of theirstereoisomers, preferably enantiomers or diastereomers, their racematesor in form of a mixture of at least two of its stereoisomers, preferablyenantiomers or diastereomers, in any mixing ratio, or salts, preferablyphysiologically acceptable salts thereof, or corresponding solvates,respectively.

Also preferred are compounds of general formula (I), wherein crepresents 0, 1 or 2, preferably 0 or 1 and R¹—R⁴, R⁵, R⁶—R⁸, A, a and bhave the meaning given above, optionally in form of one of theirstereoisomers, preferably enantiomers or diastereomers, their racematesor in form of a mixture of at least two of its stereoisomers, preferablyenantiomers or diastereomers, in any mixing ratio, or salts, preferablyphysiologically acceptable salts thereof, or corresponding solvates,respectively.

Also preferred are compounds of general formula (I), wherein at leastone of the substituents R¹, R², R³ and R⁴ represents —OR⁸ and the othersubstituents of R¹, R², R³ and R⁴ and R⁵, R⁶—R⁸, A, a, b and c have themeaning given above, optionally in form of one of their stereoisomers,preferably enantiomers or diastereomers, their racemates or in form of amixture of at least two of its stereoisomers, preferably enantiomers ordiastereomers, in any mixing ratio, or salts, preferably physiologicallyacceptable salts thereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (I), wherein one or twoof the substituents R¹, R², R³ and R⁴ represent —OR⁸ and the othersubstituents of R¹, R², R³ and R⁴ and R⁵, R⁶—R⁸, A, a and b have themeaning given above, optionally in form of one of their stereoisomers,preferably enantiomers or diastereomers, their racemates or in form of amixture of at least two of its stereoisomers, preferably enantiomers ordiastereomers, in any mixing ratio, or salts, preferably physiologicallyacceptable salts thereof, or corresponding solvates, respectively.

Also preferred are compounds of general formula (I), wherein one or twoof the substituents R¹, R², R³ and R⁴ represent —OR⁸ and b and c eachrepresent 0,

more peferably one of the substituents R¹, R², R³ and R⁴ represents —OR⁸and b and c each represent 0 and in each case the other substituents ofR¹, R², R³ and R⁴ and R⁵, R6—R⁸, A and a have the meaning given above,optionally in form of one of their stereoisomers, preferably enantiomersor diastereomers, their racemates or in form of a mixture of at leasttwo of its stereoisomers, preferably enantiomers or diastereomers, inany mixing ratio, or salts, preferably physiologically acceptable saltsthereof, or corresponding solvates, respectively.

Most preferred are 1,4-disubstituted piperidine compounds of generalformula (I) selected from the group consisting of:

-   [1]    2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,-   [2]    2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,-   [3]    2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,-   [4]    2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,-   [5]    2-[4-(3-Hydroxy-2-hydroxymethyl-phenylaminoypiperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,-   [6]    2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,-   [7]    2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide    and-   [8] 2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-I    -yl]-N-(9-ethyl-9H-carbazol-3-yl )-acetamide,

optionally in form of a salt, preferably a physiologically acceptablesalt, more preferably in form of a physiologically acceptable acidaddition salt, most preferably a hydrochloride salt, or a correspondingsolvate.

In a further aspect the present invention also provides a process forthe preparation of 1,4-disubstituted piperidine compounds of generalformula (I), wherein at least one compound of general formula (II),

wherein R⁵, R⁶ and R⁷, b and c have the meaning given above; is reactedwith at least one compound of general formula (III),

wherein A has the meaning according given above, F represents halogen,preferably chlorine, hydroxy or an O-acyl group and G representshalogen, preferably chlorine, in a suitable reaction medium andpreferably in the presence of at least one base and/or at least oneauxiliary agent, and reacting the so obtained compound of general (IV)

wherein A, G, R⁵ ₁ R⁶ and R⁷, b and c have the above defined meaning,with at least one piperidine compound of general formula (V) and/or asalt, preferably a hydrochloride salt thereof,

wherein R¹ to R⁴ and a have the meaning given above, in a suitablereaction medium, optionally in the presence of at least one base and/orat least one auxiliary agent, to yield a compound of general formula(I), wherein R¹—R⁷, A, a, b and c have the meaning as given above.

According to the invention, the process may be illustrated as an exampleby the following reaction scheme 1:

wherein R¹—R⁷ ₁ A, a, b and c have the meaning as given above.

Suitable reaction media are e.g. organic solvents, such as ethers,preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycolether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol,butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene,toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenatedhydrocarbons, e.g. dichloromethane, trichloromethane,tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzeneor/and other solvents, preferably ethyl acetate, triethylamine,pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide,acetonitril, acetone or nitromethane, are included. Mixtures based oneor more of the aforementioned solvents may also be used.

Bases that may be used in the processes according to the presentinvention are generally organic or inorganic bases, preferably alkalimetal hydroxides, e.g. sodium hydroxide or potassium hydroxide, orobtained from other metals such as barium hydroxide or differentcarbonates, preferably potassium carbonate, sodium carbonate, calciumcarbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide,sodium ethoxide, potassium methoxide, potassium ethoxide or potassiumtert-butoxide, or organic amines, preferably triethylamine,diisopropyethylamine or heterocycles, e.g. 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene pyridine, diamino pyridine,dimethylaminopyridine, methylpiperidine or morpholine. Alkali metals andtheir hydrides such as sodium or its hydrides, e.g. sodium hydride, mayalso be used. Mixtures based one or more of the aforementioned bases mayalso be used.

The above mentioned bases may be used for the process as auxiliaryagents, when appropriate. Other suitable auxiliary agents for the abovementioned reactions are, for example, dehydrating agents likecarbodiimides, e.g. diisopropylcarbodiimide, cyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, orcarbonylic compounds, e.g. carbonyidiimidazol or compounds likeisobutylchloroformiate or methansulfonyl chloride, among others. Thesereagents are generally used in amounts from 0.5 to 5 mol versus 1 mol ofthe corresponding reactands. These bases are generally used in amountsfrom 0.05 to 10 mol versus 1 mol of the corresponding reactands.

During some of the synthetic reactions described or while preparing thecompounds of general formulas (I), (II), (Ill), (IV), and (V) theprotection of sensitive groups or of reagents may be necessary and/ordesirable. This can be performed by using conventional protective groupslike those described in the literature, e.g. in Protective groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene& P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991. The protective groups may also be eliminated as convenientby means well-known to those skilled in the art. The respective parts ofthe literature description are hereby incorporated by reference and formpart of the present disclosure.

The compounds of general formulas (II), (Ill), (IV) and (V) are eithercommercially available or can be produced according to methods known tothose skilled in the art. The reaction of compounds of general formulas(IV) and (V) to yield 1,4-disubstituted piperidine compounds of generalformula (I) may also be facilitated by conventional methods known tothose skilled in the art.

The compounds of general formula (IV) are commercially available or maybe produced by conventional methods known to those skilled in the art.In particular, the respective compound of general formula (II) may bereacted with chloroacetyl chloride or the respective compound of generalformula (III) in the presence of an organic reaction medium, preferablydichloromethane and a base, preferably triethylamine and/ordiisopropylethylamine as depicted in scheme 2.

The preparation of compounds of general formula (Va), wherein R¹—R⁴ havethe meaning as given above and their use for the preparation ofcompounds of general formula (I) is illustrated in scheme 3 given below:

In a further aspect the present invention also provides a process forthe preparation of salts of 1,4-disubstituted piperidine compounds ofgeneral formula (I), wherein at least one compound of general formula(I) is reacted with an inorganic and/or organic acid, preferably in thepresence of a suitable reaction medium. Suitable reaction media are theones given above. Suitable inorganic acids are for example hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid,suitable organic acids are e.g. citric acid, maleic acid, fumaric acid,tartaric acid, or derivatives thereof, such as p-toluenesulfonic acid,methanesulfonic acid or camphersulfonic acid.

In yet a further aspect the present invention also provides a processfor the preparation of salts of 1,4-disubstituted piperidine compoundsof general formula (I), wherein at least one compound of general formula(I) having at least one acidic group is reacted with one or moresuitable bases, preferably in the presence of a suitable reactionmedium. Suitable bases are e.g. hydroxides, carbonates or alkoxides,which include suitable cations, derived e.g. from alkaline metals,alkaline earth metals or organic cations, e.g. [NH_(n)R_(4-n)]⁺, whereinn is 0, 1, 2, 3 or 4 and R represents a branched or unbranchedC₁₋₄-alkyl-radical.

Solvates, preferably hydrates, of the 1,4-disubstituted piperidinecompounds of general formula (I), or corresponding stereoisomers, orcorresponding salts may also be obtained by standard procedures known tothose skilled in the art.

If the 1,4-disubstituted piperidine compounds of general formula (I) areobtained in form of a mixture of stereoisomers, particularly enantiomersor diastereomers, said mixtures may be separated by standard proceduresknown to those skilled in the art, e.g. chromatographic methods orcrystallization with chiral reagents.

The purification and isolation of the 1,4-disubstituted piperidinecompounds of general formula (I) or a corresponding stereoisomer, or acorresponding salt, or corresponding solvate respectively, if required,may be carried out by conventional methods known to those skilled in theart, e.g. chromatographic methods or recrystallization.

The 1,4-disubstituted piperidine compounds of general formula (I), theirstereoisomers or the respective salts or solvates are toxicologicallyacceptable and are therefore suitable as pharmaceutical activesubstances for the preparation of medicaments.

Surprisingly, it has been found that the 1,4-disubstituted piperidinecompounds of general formula (I) have affinity for neuropeptide Yreceptors, in particular for neuropeptide Y 5 (NPY5) receptors.Moreover, the compounds according to the present invention havesurprisingly been found to show significant appetite suppressing effectsin rats, if administered orally or parenterally. It is particularlysuprising that the compounds of general formula (I) arepharmacologically active, if administered orally.

The present invention therefore also provides for a medicamentcomprising at least one 1,4-disubstituted piperidine compound of generalformula (I), optionally in form of one of its stereoisomers, preferablyenantiomers or diastereomers, its racemate or in form of a mixture of atleast two of its stereoisomers, preferably enantiomers or diastereomers,in any mixing ratio, or a physiologically acceptable salt thereof, or asolvate, respectively, and optionally one or more pharmaceuticallyacceptable adjuvants.

Furthermore, the present invention also provides for a pharmaceuticalcomposition comprising at least one 1,4-disubstituted piperidinecompound of general formula (I), optionally in form of one of itsstereoisomers, preferably enantiomers or diastereomers, its racemate orin form of a mixture of at least two of its stereoisomers in any mixingratio, or a physiologically acceptable salt thereof, or a solvate,respectively, and optionally one or more pharmaceutically acceptableadjuvants, which is not yet formulated into a medicament.

Preferably the medicament is suitable for the regulation of neuropeptideY receptors, preferably of neuropeptide Y 5 (NPY5) receptor, for theregulation of appetite, for the regulation of body weight, for theprophylaxis and/or treatment of disorders related to food ingestion,preferably selected from the group consisting of obesity, anorexia,cachexia, bulimia, diabetes (particularly type (II) diabetes), for theimprovement of cognition (cognitive enhancement); for the prophylaxisand/or treatment of disorders of the peripheral nervous system; for theprophylaxis and/or treatment of disorders of the central nervous system;for the prophylaxis and/or treatment of arthritis; for the prophylaxisand/or treatment of epilepsy; for the prophylaxis and/or treatment ofanxiety; for the prophylaxis and/or treatment of depression; for theprophylaxis and/or treatment of cognitive disorders, more preferablymemory disorders; for the prophylaxis and/or treatment of cardiovasculardiseases; for the prophylaxis and/or treatment of pain; for theprophylaxis and/or treatment of hypertensive syndrom; for theprophylaxis and/or treatment of inflammatory diseases; for theprophylaxis and/or treatment of immune diseases; for the prophylaxisand/or treatment of panic attacks; and for the prophylaxis and/ortreatment of bipolar disorders.

The present invention also provides for the use of at least one1,4-disubstituted piperidine compound of general formula (I), optionallyin form of one of its stereoisomers, preferably enantiomers ordiastereomers, its racemate or in form of a mixture of at least two ofits stereoisomers, preferably enantiomers or diastereomers, in anymixing ratio, or a physiologically acceptable salt thereof, or asolvate, respectively, for the manufacture of a medicament for theregulation of neuropeptide Y receptors, preferably of neuropeptide Y 5(NPY5) receptor, for the regulation of appetite, for the regulation ofbody weight, for the prophylaxis and/or treatment of disorders relatedto food ingestion, preferably selected from the group consisting ofobesity, anorexia, cachexia, bulimia, diabetes (particularly type (II)diabetes), for the improvement of cognition (cognitive enhancement); forthe prophylaxis and/or treatment of disorders of the peripheral nervoussystem; for the prophylaxis and/or treatment of disorders of the centralnervous system; for the prophylaxis and/or treatment of arthritis; forthe prophylaxis and/or treatment of epilepsy; for the prophylaxis and/ortreatment of anxiety; for the prophylaxis and/or treatment ofdepression; for the prophylaxis and/or treatment of cognitive disorders,preferably memory disorders; for the prophylaxis and/or treatment ofcardiovascular diseases; for the prophylaxis and/or treatment of pain;for the prophylaxis and/or treatment of hypertensive syndrom; for theprophylaxis and/or treatment of inflammatory diseases; for theprophylaxis and/or treatment of immune diseases; for the prophylaxisand/or treatment of panic attacks; and for the prophylaxis and/ortreatment of bipolar disorders.

The medicament according to the present invention is particularlysuitable for the administration to mammals, including humans. Themedicament can be administered to patients of all ages, namely children,adolescents and adults. The composition of the medicament may varydepending on the route of administration.

The preparation of the corresponding pharmaceutical compositions as wellas the formulated medicaments can be carried out by means ofconventional methods known in the prior art, for example, from theindices of “Pharmaceutics: The Science of Dosage Forms”, Second Edition,Aulton, M. E. (ED. Churchill Livingstone, Edinburgh (2002));“Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick,J. and Boylan, J. C. (Eds.), Marcel Dekker, Inc. New York (2002);“Modern Pharmaceutics”, Fourth Edition, Banker G. S. and Rhodes C. T.(Eds.) Marcel Dekker, Inc. New York (2002), and “The Theory and Practiceof Industrial Pharmacy”, Lachman L., Lieberman H. and Kanig J. (Eds.),Lea & Febiger, Philadelphia (1986). The respective literaturedescriptions are incorporated as a reference and are part of thisdisclosure.

The pharmaceutical compositions, as well as the formulated medicamentsprepared according to the present invention, can, in addition to atleast one compound of general formula (I), optionally in the form of oneof its stereoisomers, preferably enantiomers or diastereomers, itsracemate, or in form of a mixture of at least two of its stereoisomers,preferably enantiomers or diastereomers, in any mixing ratio, or acorresponding physiologically acceptable salt thereof or a correspondingsolvate thereof, comprise other conventional auxiliary substances knownin the prior art, preferably excipients, fillers, solvents, diluents,dyes, coating agents, matrix forming agents and/or binders.

As the skilled persons in the art also knows, the choice of theauxiliary substances and the amounts thereof depend on the intendedadministration route, for example, rectal, intravenous, intraperitoneal,intramuscular, intranasal, oral, buccal or topical.

Medicaments suitable for oral administration are, for example, tablets,coated tablets, capsules or multiparticulates, preferably granules orpellets, optionally compressed into tablets, filled in capsules orsuspended in suitable liquids.

Medicaments suitable for parenteral, topical or inhalatoryadministration may preferably be chosen from the group consisting ofsolutions, suspensions, quickly reconstitutable dry preparations andalso sprays.

Medicaments suitable for oral or percutaneous use can release thecompounds of general formula (I) in a sustained manner, the preparationof these sustained release medicaments generally being known in theprior art.

Suitable sustained release forms, as well as the materials and methodsfor the preparation thereof, are known in the prior art, for examplefrom the indices of “Modified-Release Drug Delivery Technology”,Rathbone, J. Jl, Hadgraft, J. and Roberts, M. S. (Eds.), Marcel Dekker,Inc., New York (2002); “Handbook of Pharmaceutical Controlled ReleaseTechnology”, Wise, D. L. (Ed.), Marcel Dekker, Inc. New York (2000);“Controlled Drug Delivery”, Vol. I, Basic Concepts, Bruck, S. D. (Ed.),CRD Press, Inc., Boca Raton (1983), and by Takada, K. and Yoshikawa, H.,“Oral Drug Delivery”, Encyclopedia of Controlled Drug Delivery,Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2,728-742; Fix, J., “Oral drug delivery, small intestine and colon”,Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), JohnWiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respectiveliterature references are incorporated by reference and form part of thedisclosure.

The medicament of the present invention may also have at least oneenteric coating, which dissolves according to the pH. As a result ofthis coating, the medicament may pass through the stomach withoutdissolving, and the compounds of general formula I are only released inthe intestinal tract. The enteric coating preferably dissolves at a pHof between 5 and 7.5. The materials and methods suitable for preparingenteric coatings are also known in the prior art.

The above mentioned compositions include preferably 1 to 60 % by weightof one or more of the 1,4-disubstituted piperidine compound of generalformula (I), optionally in form of one of its stereoisomers, preferablyenantiomers or diastereomers, its racemate or in form of a mixture of atleast two of its stereoisomers in any mixing ratio, or a physiologicallyacceptable salt thereof, or a solvate, respectively, and 40 to 99 % byweight of the appropriate pharmaceutical vehicle(s).

The daily dosage for humans and animals may vary depending on factorsthat have their basis in the respective species or other factors, suchas age, weight or degree of illness and so forth. The daily dosage formammals including humans usally ranges from 1 milligram to 5000milligram, preferably 1 to 3000 mg, more preferably 1 to 2000 mg ofsubstance to be administered during one or several intakes.

Pharmacological Methods:

Neuropeptide Y₅ Receptor Binding Studies:

The methods used for membrane preparation and binding are similar tothose described by Y. Hu, B. T. Bloomquist et al. in Y. Hu, B. T.Bloomquist et al., The Journal of Biological Chemistry, 1996, 271,26315-26319 with modifications. Said literature description is herewithincorporated by reference and forms part of the disclosure. Cells C6were transfected with the rat Y5 receptor. The cells were grown understandard culture conditions in 150 cm² dishes and they were harvestedusing a rubber scraper and 10 ml PBS. The cells from five dishes werecollected and centrifuged 2.500 g for 5 min (4° C.). The pellet waswashed by resuspending in 3 ml buffer (Tris-HCl 10 mM, pH 7.4),homogenized using a Potter S homogenizer, 10 strokes at 600 rpm andcentrifuged 48.000 g for 20 min (4° C). The pellet was resuspended in 8ml membrane buffer (Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM, KH₂PO₄ 1.2mM, CaCl₂ 2.5 mM, MgSO₄ 1.2 mM, BSA 0.15 mg/ml, Bacitracine 0.5 mg/ml,pH 7.4) and rehomogenized using the Potter S, 10 strokes at 600 rpm. Theprotein concentration in the incubation was 40 μg/ml. The radioligandwas [¹²⁵I]-PYY (100 pM) in a total incubation volume of 200 μl.Following incubation at 25° C. for 2 h, the reaction was stopped byaddition of 5 ml ice-cold buffer (Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM,KH₂PO₄ 1.2 mM, CaCl₂ 2.5 mM, MgSO₄ 1.2 mM, pH 7.4) and rapid filtrationin a Harvester Brandell Cell using filters (Schleicher & Schuell GF3362) pretreated for two hours with 0.5% polyethyleneimine. Filters werewashed one time with 5 ml ice-cold buffer. The filters were placed intoplastic scintilation vials and 5 ml scintilation cocktail Ecoscint Hwere added. The quantity of radioactivity present was determined in aWallac Winspectral 1414 counter. Non specific binding was determined inthe presence of 1 μM de pNPY. All binding assays were done intriplicate.

Behavioural Model (Food Intake Measurements)

In this test the effect of the compounds of general formula (I) on foodand water intake in male rats can be determined.

Animals:

128 male Sprague Dawley Rats (aged 6 weeks, approximately 190 g;obtained from Charles River, Germany) were used. The rats arrived 32 ata time. Upon arrival they were be housed 3 per cage for one week andsubsequently transferred to individual cages mounted with feederscontaining powdered chow. During the single housing period, rats werehandled daily to accustom them to the injection procedure. From thearrival date, rats are kept under a 12/12 L/D cycle lights on at 0300and in temperature and humidity controlled rooms.

Treatment Groups and Randomization

Two weeks after the arrival, the rats were transferred to MANI Feedwincages and randomized into 4 weight-matched groups, that is 8 rats pergroup. Rats had ad libitum access to a powdered diet (Atromin rodentchow, C. Petersen Ringsted) and tap water. In addition, body weight wasmonitored daily.

Rats were subjected to a maximum of 4 injections, each separated by atleast 3 days. If carry over effects were still present at that timeinjections were postponed further. All compounds were administered inthree doses: 5, 30 and 60 mg/kg. All compounds were administered p.o. bygavage (gavage volume of 5-8 ml/kg, determined by the solubility of thecompound).

Group 1 Vehicle

Group 2 testing compound (I) 5 mg/kg

Group 3 testing compound (I) 30 mg/kg

Group 4 testing compound (I) 60 mg/kg

Experimental Procedure

For 2 days prior to transfer to the MANI Feedwin cages, in addition tothe daily handling procedure rats were gavaged daily with vehicle.Baseline food intake (digital balance) and lick counts were monitoredfrom day 1 to day 3. First day of injection was day 3. Prior to lightsout (14.30 PM) the rats were administered the testing compound andvehicle by gavage. Food intake (digital balance) and water intake(registered as lick counts) were monitored online every 5^(th) minutefor 48 hours following the time of injection or until the effect of thedrug had worn off.

Testing compounds (I) with significant appetite suppressing effects,i.e. effective compounds, at any of the following time points 1, 4, 6,12, 18, 24, 48 h after the injection were re-administered to the samegroup of rats in a randomized manner so that no rat received the samedosage twice.

In addition, the following analysis was carried out for effectivetesting compounds:

Locomotor activity (consecutive beam streaks) analyzed for 48 hoursfollowing administration of the testing compounds at the same time asfood intake was registered

Meal microstructure analysis based on the food and licking data from theexperiment in 5 minutes intervals. The meal size, the meal duration, theinterval between two meals and the meal numbers was analyzed during thefirst 24 hours after administration.

The following examples are given to illustrate the present invention,but they do not limit the scope of the present invention.

EXAMPLES Example A:

2-Chloro-N-(9-methyl-9H-carbazol-3-yl)-acetamide

A solution of 3-amino-9-methyl-9H-carbazol (10 mmols ), triethylamine(2.07 ml, 15 mmols), in 25 ml of dried dichloromethane, is cooled to 10°C. and a solution of chloroacetyl chloride (10.5 mmoles) in 10 ml ofdried dichloromethane is then added drop by drop. The resulting mixtureis kept stirring for 1 hour at room temperature overnight. The mixtureis washed with 2×30 ml of water, dried over sodium sulfate andevaporated to give 2.5 g of2-Chloro-N-(9-methyl-9H-carbazol-3-yl)-acetamide.

Example 1

2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide

Step a)

A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (0.01 mol),3-Amino-2-hydroxymethyl-phenol (0.011 mol) and acetic acid (1.4 ml,0.022 mol) in dried toluene (50 mL) were heated to reflux, removing thewater by means of azeotropic distillation with a Dean-Stark, over 30hours. Then, the mixture was cooled and concentrated under vacuum to thehalf of the volume. NaBH₃CN (2 g, 0.032 mol) and dried THF (30 mL) isadded to a resulting solution.

Afterwards, acetic acid (1 mL, 0.017 mol) was added slowly and thereaction mixture was stirred at room temperature over 24 hours. Themixture was concentrated under vacuum and the residue was dissolved inethyl acetate (75 mL), washed with a saturated NaHCO₃ (4×25 mL) and asaturated NaCl solution (25 mL), dried and evaporated to dryness. Thisraw material was used in the following step.

Step b)

A solution of 3.2 g of the raw material obtained in the previous step a)in 40 mL of dried ethyl acetate, was cooled to 0° C. Then a 5 M hydrogenchloride solution in ethyl ether (40 mL) was added and the resultingmixture was kept at 0° C. over 4 hours. The solvent was evaporated andthe residue was suspended in water and was alcalinized with sodiumhydroxide, and was extracted with chloroform (3×20 mL), the combinedorganic extracts were washed with water, dried over sodium sulfate andevaporated. The raw material was purified via column cromatography byeluting with chloroform:methanol 9:1 (vol/vol). In this way 1.3 g of ayellow solid were obtained.

Step c)

A mixture of 3-N-(4-Amino-piperidin)-2-hydroxymethyl-phenol (4.70 mmol),2-Chloro-N-(9-methyl-9H-carbazol-3-yl)-acetamide (5 mmol) and K₂CO₃(1380 mg, 10 mmol) in DMF (40 mL) was stirred at 10° C. for 2 hours andthen at room temperature overnight. The reaction mixture was added to 50mL water and 100 mL ethyl acetate, the organic phase was decanted andwashed with water ( 3×50 mL), dried over sodium sulfate and a 2.8 Mhydrogen chloride solution in absolute ethanol (1.80 mL) was added, toprecipitate the hydrochloride, which was filtered off and washed withethyl acetate to obtain the compound2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamidewith a yield of 70%.

The compounds according to the following examples 2-8 have been preparedas described above for the compound according to example 1.

Example 2

2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide

Example 3

2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide

Example 4

2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide

Example 5

2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide

Example 6

2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide

Example 7

2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide

Example 8

2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide.

1. 1,4-disubstituted piperidine compounds of general formula (I),

wherein a represents 0, 1, 2, 3 or 4, b represents 0, 1, 2 or 3, crepresents 0, 1, 2, 3 or 4, R¹, R², R³, R⁴ are each independentlyselected from the group consisting of hydrogen; halogen; —CN; —NO₂;—OR⁸; a linear or branched, saturated or unsaturated, optionally atleast mono-substituted aliphatic radical; a saturated or unsaturated,optionally at least mono-substituted, optionally at least one heteroatomas ring member containing cycloaliphatic radical, which may be bondedvia an alkylene group; or an optionally at least mono-substituted aryl-or heteroaryl radical, which may be bonded via an alkylene group and/orwhich may be condensed with an optionally at least mono-substituted,saturated or unsaturated mono- or bicyclic ring system, R⁵ representshydrogen, a linear or branched, saturated or unsaturated, optionally atleast mono-substituted aliphatic radical, or a saturated or unsaturated,optionally at least mono-substituted cycloaliphatic radical, R⁶, R⁷ andR⁸, identical or different, each represent hydrogen or a prodrug-moiety,A represents a —CH₂— or —CH₂—CH₂— group, optionally in form of one ofits stereoisomers, preferably enantiomers or diastereomers, its racemateor in form of a mixture of at least two of its stereoisomers, preferablyenantiomers or diastereomers, in any mixing ratio, or a salt, preferablya physiologically acceptable salt thereof, or a corresponding solvate,respectively.
 2. Compounds according to claim 1, characterized in thatR¹, R², R³, R⁴ are each independently selected from the group consistingof H; F; Cl; Br; —CN; —NO₂; —OR⁸; a linear or branched, saturated orunsaturated, optionally at least mono-substituted C₁₋₆-aliphaticradical; a saturated or unsaturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₃₋₈-cycloaliphatic radical, which may be bonded via aC₁₋₃-alkylene group; or an optionally at least mono-substituted aryl- orheteroaryl radical, which may be bonded via a C₁₋₃-alkylene group and/orwhich may be condensed with an optionally at least mono-substituted,saturated or unsaturated mono- or bicyclic ring system, R⁵ representshydrogen, a linear or branched, saturated or unsaturated, optionally atleast mono-substituted C₁₋₆-aliphatic radical, or a saturated orunsaturated, optionally at least mono-substituted C₃₋₈-cycloaliphaticradical, R⁶, R⁷ and R⁸, identical or different, each represent hydrogenor a prodrug-moiety, A represents a —CH₂— or —CH₂—CH₂— group. 3.Compounds according to claim 1 or 2, characterized in that R¹, R², R³,R⁴ are each independently selected from the group consisting of H; F;Cl; Br; —CN; —NO₂; —OR⁸; a linear or branched, optionally at leastmono-substituted C₁₋₄-alkyl radical, a saturated, optionally at leastmono-substituted, optionally at least one heteroatom as ring membercontaining C₅- or C₆-cycloaliphatic radical, which may be bonded via anoptionally at least mono-substituted C₁- or C₂-alkylene group;preferably R¹, R², R³, R⁴ are each independently selected from the groupconsisting of H; F; Cl; Br; —CN; —NO₂; —CH₃; —CH₂CH₃; —CHF₂; —CH₂F;—CF₃; —CF₂CF₃; OR⁸; cyclopentyl and cyclohexyl, more preferably R¹, R²,R³, R⁴ are each independently selected from the group consisting of H;F; Cl; Br, CH₃ and OR⁸.
 4. Compounds according to any one of claims 1 to3, characterized in that R⁵ represents H or a linear or branched C₁₋₆alkyl radical, preferably R⁵ represents H or an alkyl radical selectedfrom the group consisting of methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl and tert-butyl.
 5. Compounds according toany one of claims 1 to 4 characterized in that R⁶, R⁷ and R⁸, identicalor different, each represent H or a prodrug-moiety selected from thegroup consisting of linear or branched C₁₋₃-alkyl, a P(═O)(OR⁹)₂ group,wherein R⁹ represents a linear or branched C₁₋₄-alkyl radical, a—(C═O)—O—R¹⁰ group, wherein R¹⁰ represents a linear or branchedC₁₋₅-alkyl radical, a —(C═O)—NH—R¹¹ group, wherein R¹¹ represents aphenyl group, which is mono-substituted with a linear or branched C₁₋₃alkyl radical, a —(C═O)—R¹² group, wherein R¹² represents a phenylgroup, which is mono-substituted with a —O—(C═O)—C₁₋₃-alkyl radical, an—CH₂—N(C₁₋₄-alkyl)₂ group or a


6. Compounds according to claim 5, characterized in that R⁶, R⁷ and R⁸,identical or different, each represent H or a prodrug-moiety selectedfrom the group consisting of linear or branched alkyl selected from thegroup consisting of methyl, ethyl, n-propyl and iso-propyl, aP(═O)(OR⁹)₂ group, wherein R⁹ represents methyl or ethyl, a —(C═O)—O—R¹⁰group, wherein R¹⁰ represents an alkyl radical selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl and tert-butyl, a —(C═O)—NH—R¹¹ group, wherein R¹¹ representsa phenyl group, which is mono-substituted with methyl or ethyl, a—(C═O)—R¹² group, wherein R¹² represents a phenyl group, which ismono-substituted with —O—(C═O)—C₁₋₃-alkyl radical in the ortho positionor with an —CH₂—N(C₁₋₄-alkyl)₂ in the meta or para position or with a

in the meta or para position.
 7. Compounds according to any one ofclaims 1-6, characterized in that R⁶, R⁷ and R⁸ each represent hydrogen.8. Compounds according to any one of claims 1 to 7, characterized inthat A represents a —CH₂— group.
 9. Compounds according to any one ofclaims 1 to 8, characterized in that a represents 1, 2 or 3, preferably1 or 2, more preferably
 1. 10. Compounds according to any one of claims1 to 9, characterized in that b represents 0, 1 or 2, preferably 0 or 1.11. Compounds according to any one of claims 1 to 10, characterized inthat c represents 0, 1 or 2, preferably 0 or
 1. 12. Compounds accordingto any one of claims 1 to 11, characterized in that at least one of thesubstituents R¹, R², R³ and R⁴ represents —OR⁸.
 13. Compounds accordingto any one of claims 1 to 12, characterized in that one or two of thesubstituents R¹, R², R³ and R⁴ represent —OR⁸.
 14. Compounds accordingto any one of claims 1 to 13, characterized in that one or two of thesubstituents R¹, R², R³ and R⁴ represent —OR⁸ and b and c each represent0, more peferably one of the substituents R¹, R², R³ and R⁴ represents—OR⁸ and b and c each represent
 0. 15. Compounds according to any one ofclaims 1-14 selected from the group consisting of: [1]2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,[2]2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,[3]2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-ylacetamide, [4]2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-methyl-9H-carbazol-3-yl)-acetamide,[5]2-[4-(3-Hydroxy-2-hydroxymethyl-phenylamino)piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,[6]2-[4-(4-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,[7]2-[4-(5-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamideand [8]2-[4-(6-Hydroxy-2-hydroxymethyl-phenylamino)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,optionally in form of a salt, preferably a physiologically acceptablesalt, more preferably in form of a physiologically acceptable acidaddition salt, most preferably a hydrochloride salt, or a correspondingsolvate.
 16. Process for the preparation of 1,4-disubstituted piperidinecompounds according to one or more of claims 1-15, characterized in thatat least one compound of general formula (II),

wherein R⁵, R⁶ and R⁷, b and c have the meaning according to one or moreof claims 1-15; is reacted with at least one compound of general formula(III),

wherein A has the meaning according to one or more of claims 1-15, Frepresents halogen, preferably chlorine, hydroxy or an O-acyl group andG represents halogen, preferably chlorine, in a suitable reaction mediumand preferably in the presence of at least one base and/or at least oneauxiliary agent, and reacting the so obtained compound of general (IV)

wherein A, G, R⁵, R⁶ and R⁷, b and C have the above defined meaning,with at least one piperidine compound of general formula (V) and/or asalt, preferably hydrochloride, thereof,

wherein R¹ to R⁴ and a have the meaning according to one or more ofclaims 1-15, in a suitable reaction medium, optionally in the presenceof at least one base and/or at least one auxiliary agent.
 17. Processfor the preparation of a physiologically acceptable salt of the1,4-disubstituted piperidine compounds according to claims 1-15,characterized in that at least one compound of general formula (I) isreacted with at least one acid, preferably an inorganic or organic acid,preferably in the presence of a suitable reaction medium.
 18. Processfor the preparation of a physiologically acceptable salt of the1,4-disubstituted piperidine compounds according to claims 1-15,characterized in that at least one compound of general formula (I)having at least one acidic group is reacted with at least one base,preferably in the presence of a suitable reaction medium.
 19. Medicamentcomprising at least one 1,4-disubstituted piperidine compound accordingto any one of claims 1-15 and optionally one or more pharmaceuticallyacceptable adjuvants.
 20. Medicament according to claim 19 for theregulation of appetite, for the regulation of body weight, for theprophylaxis and/or treatment of disorders related to food ingestion,preferably selected from the group consisting of obesity, anorexia,cachexia, bulimia and/or diabetes (particularly type (II) diabetes). 21.Medicament according to claim 19 for the improvement of cognition(cognitive enhancement); for the prophylaxis and/or treatment ofdisorders of the peripheral nervous system; for the prophylaxis and/ortreatment of disorders of the central nervous system; for theprophylaxis and/or treatment of arthritis; for the prophylaxis and/ortreatment of epilepsy; for the prophylaxis and/or treatment of anxiety;for the prophylaxis and/or treatment of depression; for the prophylaxisand/or treatment of cognitive disorders, preferably memory disorders;for the prophylaxis and/or treatment of cardiovascular diseases; for theprophylaxis and/or treatment of pain; for the prophylaxis and/ortreatment of hypertensive syndrom; for the prophylaxis and/or treatmentof inflammatory diseases; for the prophylaxis and/or treatment of immunediseases; for the prophylaxis and/or treatment of panic attacks and/orfor the prophylaxis and/or treatment of bipolar disorders.
 22. Use of atleast one 1,4-disubstituted piperidine compound according to any one ofclaims 1-15 for the manufacture of a medicament for the regulation ofappetite, for the regulation of body weight, for the prophylaxis and/ortreatment of disorders related to food ingestion, preferably selectedfrom the group consisting of obesity, anorexia, cachexia, bulimia anddiabetes (particularly type (II) diabetes).
 23. Use of at least one1,4-disubstituted piperidine compound according to any one of claims1-15 for the manufacture of a medicament for the improvement ofcognition (cognitive enhancement); for the prophylaxis and/or treatmentof disorders of the peripheral nervous system; for the prophylaxisand/or treatment of disorders of the central nervous system; for theprophylaxis and/or treatment of arthritis; for the prophylaxis and/ortreatment of epilepsy; for the prophylaxis and/or treatment of anxiety;for the prophylaxis and/or treatment of depression; for the prophylaxisand/or treatment of cognitive disorders, preferably memory disorders;for the prophylaxis and/or treatment of cardiovascular diseases; for theprophylaxis and/or treatment of pain; for the prophylaxis and/ortreatment of hypertensive syndrom; for the prophylaxis and/or treatmentof inflammatory diseases; for the prophylaxis and/or treatment of immunediseases; for the prophylaxis and/or treatment of panic attacks and forthe prophylaxis and/or treatment of bipolar disorders.